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The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress.Nature and science of sleepChow, M., Cao, M.2016; 8: 81-86

Abstract

Much of the understanding of the hypocretin/orexin (HCRT/OX) system in sleep-wake regulation came from narcolepsy-cataplexy research. The neuropeptides hypocretin-1 and -2/orexin-A and -B (HCRT-1 and -2/OX-A and -B, respectively), as we know, are intimately involved in the regulation wakefulness. The HCRT/OX system regulates sleep-wake control through complex interactions between monoaminergic/cholinergic (wake-promoting) and gamma-aminobutyric acid-ergic (sleep-promoting) neuronal systems. Deficiency of HCRT/OX results in loss of sleep-wake control or stability with consequent unstable transitions between wakefulness to nonrapid eye movement and rapid eye movement sleep. This manifests clinically as abnormal daytime sleepiness with sleep attacks and cataplexy. Research on the development of HCRT/OX agonists and antagonists for the treatment of sleep disorders has dramatically increased with the US Food and Drug Administration approval of the first-in-class dual HCRT/OX receptor antagonist for the treatment of insomnia. This review focuses on the origin, mechanisms of HCRT/OX receptors, clinical progress, and applications for the treatment of sleep disorders.

Abstract

Mutual interactions between neurohormones, sleep, and the circadian system have been extensively studied. Hormonal secretion is either influenced by sleep and is independent of circadian timing or is closely coupled with the light-dark cycle, although both processes ultimately interact with each other. Sleep has a strong effect on the levels of some hormones (e.g., growth hormone) but little effect on others that are primarily regulated by the circadian system (e.g., melatonin). The exact mechanisms through which sleep affects circulating hormonal levels are not well understood. Much more is known about how the circadian system influences the secretion of hormones. Under normal circumstances, behaviors and the circadian system are synchronized with an optimal phase relationship, and consequently, hormonal systems are exquisitely regulated. Every bit of information constitutes but one small component of a broader, more global neurohormonal picture. In this review, we attempt to divide this analysis into sections including the pineal gland, adenohypophysis, neurohypophysis, describing the reciprocal influence regarding sleep and various neurohormones.

Abstract

Hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep through stabilization of sleep promoting GABAergic and wake promoting cholinergic/monoaminergic neural pathways. Hypocretin also influences other physiologic processes such as metabolism, appetite, learning and memory, reward and addiction, and ventilatory drive. The discovery of hypocretin and its effect upon the sleep-wake cycle has led to the development of a new class of pharmacologic agents that antagonize the physiologic effects of hypocretin (i.e. hypocretin antagonists). Further investigation of these agents may lead to novel therapies for insomnia without the side-effect profile of currently available hypnotics (e.g. impaired cognition, confusional arousals, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle while also influencing non-sleep physiologic processes may create an entirely different but equally concerning side-effect profile such as transient loss of muscle tone (i.e. cataplexy) and a dampened respiratory drive. In this review, we will discuss the discovery of hypocretin and its receptors, hypocretin and the sleep-wake cycle, hypocretin antagonists in the treatment of insomnia, and other implicated functions of the hypocretin system.

Hypocretin and Its Emerging Role as a Target for Treatment of Sleep DisordersCURRENT NEUROLOGY AND NEUROSCIENCE REPORTSCao, M., Guilleminault, C.2011; 11 (2): 227-234

Abstract

The neuropeptides hypocretin-1 and -2 (orexin A and B) are critical in the regulation of arousal and maintenance of wakefulness. Understanding the role of the hypocretin system in sleep/wake regulation has come from narcolepsy-cataplexy research. Deficiency of hypocretin results in loss of sleep/wake control with consequent unstable transitions from wakefulness into non-rapid eye movement (REM) and REM sleep, and clinical manifestations including daytime hypersomnolence, sleep attacks, and cataplexy. The hypocretin system regulates sleep/wake control through complex interactions between monoaminergic/cholinergic wake-promoting and GABAergic sleep-promoting neuronal systems. Research for the hypocretin agonist and the hypocretin antagonist for the treatment of sleep disorders has vigorously increased over the past 10 years. This review will focus on the origin, functions, and mechanisms in which the hypocretin system regulates sleep and wakefulness, and discuss its emerging role as a target for the treatment of sleep disorders.

Abstract

The use of opioids has been associated with development of sleep-disordered breathing, including central apneas, nocturnal oxygen desaturations, and abnormal breathing patterns. We describe sleep-disordered breathing and its subsequent treatment in a group of obstructive sleep apneic patients on chronic opioid therapy. Clinical evaluation followed by diagnostic overnight polysomnogram was performed in subjects on chronic opioid therapy who met the study criteria. All subjects had an initial CPAP titration followed by a repeat clinical evaluation. Subjects with an apnea-hypopnea index (AHI) ? 5 continued to report symptoms and had follow-up titration with bilevel positive therapy; then bilevel positive-pressure therapy with a back-up rate was then performed. Age-, sex-, and disease-severity-matched obstructive sleep apnea patients served as controls. Forty-four study participants, including a large group of women (50%), and 44 controls were enrolled in the study. Opioid subjects had AHI = 43.86 ± 1.19, with a central apnea index of 0.64 ± 1.36. Two abnormal breathing patterns were seen, including decreased inspiratory effort during an obstructive event and longer than expected pauses in breathing. Despite adequate titration with CPAP and bilevel positive-pressure therapy, nocturnal awakenings and central apnea awakenings persisted (AHI and central apnea indices of 13.81 ± 2.77 and 11.52 ± 2.12, respectively). Treatment with bilevel positive-pressure therapy with a back-up rate controlled the problem. Nonobese OSA patients with opioid intake have obstructive breathing with a different pattern. In this study, bilevel positive-pressure therapy with a back-up rate was the most effective treatment.

Abstract

Studies on families with sleepwalking are uncommonly published but can give further information on the phenotype of patients with chronic sleepwalking.Out of 51 individuals referred for chronic sleepwalking during a 5-year period, we obtained sufficient information on 7 families with direct relatives who reported sleepwalking with or without sleep terrors. Among 70 living direct family members, we obtained questionnaire responses from 50 subjects and identified 34 cases with a history of sleepwalking. Of the 50 subjects, 16 completed only questionnaires, while all the others also completed a clinical evaluation and nocturnal sleep recordings.There was a positive history of sleepwalking on either the paternal or maternal side of the family over several generations in our 7 families. Thirty-three clinically evaluated subjects had evidence of sleep-disordered breathing (SDB), with associated craniofacial risk factors for SDB (particularly maxillary and/or mandibular deficiencies). There was a complete overlap with the report of parasomnias and the presence of SDB. In cases with current sleepwalking, treatment of SDB coincided with clear improvement of the parasomnia.All of our subjects with parasomnias presented with familial traits considered as risk factors for SDB. These anatomical risk factors are present at birth and even subtle SDB can lead to sleep disruption and instability of NREM sleep. The question raised is: are factors leading to chronic sleep disruption the familial traits responsible for familial sleepwalking?

Abstract

Narcolepsy with cataplexy is a rare but life-long and challenging disorder. Current insight into the pathophysiology of this condition seems to be autoimmune-mediated postnatal cell death of hypocretin neurons occurring by organ-specific autoimmune targeting with HLA-T-cell receptor interactions. The hypocretin system seems to have an influence on multiple organ systems beyond its wake-promoting mechanisms. The recent availability of cerebrospinal fluid hypocretin-1 analysis has led to definitive diagnostic criteria for narcolepsy with cataplexy. Pharmacologic first-line treatments for excessive daytime sleepiness and cataplexy is sodium oxybate, with modafinil for daytime sleepiness, in adults and children. Other investigative agents and treatment modalities hold promise in future directions for narcolepsy.

Abstract

The dual-wave bolus delivers a combination of an immediate normal pre-meal insulin bolus (approximately 3 min) followed by an extended (or square-wave) bolus that is evenly delivered over several hr as programmed by the patient. The purpose of this study was to compare post-prandial glycaemic excursions following a high-fat meal after administration of insulin by normal vs dual-wave bolus. During this prospective, cross-over, repeated measures study, subjects with diabetes and treated with insulin pump therapy were evaluated using the continuous glucose monitoring system (CGMS) following three combinations of meal and bolus type. A control meal or a high-fat meal was given in place of the evening meal on three separate occasions and comparisons were made between: a) the control meal with normal insulin bolus delivery, b) the high-fat meal with normal insulin bolus delivery, and c) the high-fat meal with dual-wave insulin bolus delivery. Although mean baseline CGMS values were similar in each of the three combinations of meal and bolus type (p=0.54) and in the three hr immediately following the meal (p=0.64, p=0.83, p=1.0), when compared to the control meal/normal bolus and high-fat meal/dual-wave bolus combinations, CGMS profiles disclosed significantly elevated post-prandial glucose in hr 5 through 14 (p<0.05) following the high-fat/normal bolus combination. Prolonged post-prandial glycaemic excursions are identified using the CGMS. Treating post-prandial hyperglycaemia with dual-wave insulin delivery may help manage chronic hyperglycaemia in patients with diabetes.